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In this thesis, we set out to investigate the complex relationship between endogenous sex hormones and cardiometabolic risk in men and women. The first part of this thesis is devoted to studies in women, and the second part describes the association between sex hormones and cardiometabolic risk in men. In Chapter 2 we report on the relationship between menopausal age, reproductive lifespan and type 2 diabetes risk. We studied this association in the InterAct study, a case-cohort study nested in the European Prospective Investigation in Cancer and Nutrition (EPIC). In Chapter 3 we examined whether metabolic risk accelerates menopausal onset. Here, we investigated the impact of diabetes and age at diagnosis on timing of natural menopause in the EPIC cohort. As smoking is clearly associated with menopausal age and risk of cardiometabolic ...
We investigated the role of MGP carboxylation (i.e. activation) in the association of high vitamin K intake with reduced vascular calcification and cardiovascular disease risk. We hypothesized that a high vitamin K intake will increase carboxylation of MGP, which will reduce vascular calcification and lower cardiovascular disease risk. Theoretically, low uncarboxylated and high carboxylated MGP concentrations would be associated with reduced calcification risk. However, MGP exists as various species, which differ in their state of phosphorylation and/or carboxylation: phosphorylated carboxylated (p-cMGP), phosphorylated uncarboxylated (p-ucMGP), desphospho-carboxylated MGP (dp-cMGP) and desphospho-uncarboxylated dp-ucMGP (dp-ucMGP). To date, it is possible to measure circulating dp-ucMGP, dp-cMGP and total-ucMGP (t-ucMGP), which is t...
Activities of daily living (ADL), such as bathing and doing groceries are essential for maintaining independence in the community. Previous longitudinal studies have shown that about 20 to 30% of older persons (70 years and older) experience ADL disability. Older persons who are ADL disabled have higher rates of morbidity and mortality, and have a poorer quality of life. Disability is a dynamic process in which older persons both develop disability and recover from a period of disability. The recovery rate after a first episode of disability seems to be high (81% within 12 months), yet having experienced disability is a good predictor of future disability, thus, intervention in an early stage may still prevent sustained disability. Therefore, it is important to identify risk factors in an early stage of the disabling process, that mi...
With aging, there is an increase of the incidence of frailty. Frailty is associated with adverse health outcomes, like falls and fractures, disabilities, hospitalization, institutionalization and mortality. It is generally accepted that frailty, unlike the aging process, is in part reversible and amenable to interventions. Two physical changes appear to be the main cause of frailty, namely loss of muscle mass (sarcopenia) and bone mineral density. The last decades more attention has been raised to the potential importance of androgens in etiology, prevention of treatment of frailty. In this thesis, we investigated the relation between androgens, sarcopenia, bone mineral density and frailty in men and we assessed the effects of testosteron supplementation on these parameters. For the first research question, we found that testosterone w...
A low lifetime endogenous estrogen exposure is suggested to promote cardiovascular disease and related death after menopause in women. As a logical consequence, the view that the cardiovascular disease risk might be reversed by replacing the endogenous estrogens by exogenous estrogens in the form of hormone therapy became popular. Indeed, observational studies report risk reductions up to 30-50%, but the clinical trials unexpectedly showed that hormone therapy does not provide coronary protection. However, whereas vasomotor menopausal symptoms, such as hot flushes and night sweats are the main indication for prescribing hormone therapy in the population, women with severe symptoms were either excluded in the clinical trials or comprised only a minority of the total randomized population, due to ethical reasons. We suggested previously ...
Cardiovascular disease is the leading complication of type 2 diabetes and approximately half of the patients with type 2 diabetes will die of a cardiovascular cause. To prevent the occurrence of cardiovascular disease, effective diabetes treatment is necessary. Up-titrating diabetes medication by addition of an oral drug or commencement of insulin improves glycemic control. However it has been suggested that glucose lowering agents are associated with weight gain, which could increase the incidence of cardiovascular disease. In our study medication combinations including insulin or thiazolidinedione were associated with increase in weight of 3 kg, while sulphonylureas and metformin were weight neutral. Moreover we assessed the effect of blood pressure lowering agents among moderate-high and very high cardiovascular risk groups. A...
Menopause is the endpoint of a process referred to as ovarian ageing. The mean age at menopause is approximately 51 years, but varies widely between 40 to 60 years of age. Approximately 1% of all women experience menopause before the age of 40, which is a condition known as primary ovarian insufficiency (POI). Timing of menopause has great implications for female fertility and general health (e.g. osteoporosis and cardiovascular disease). Although the exact physiological processes underlying the timing of menopause are far from elucidated at present, genetic factors have proven to play a major role in determining this variation in menopausal age. The identification of genetic variants associated with (early) ovarian ageing and thereby infertility and consequences for health later in life, constitutes the core of this thesis. To ident...
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